• Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonist.

• Clinical predictors of aripiprazole-associated worsening of psychosis include low baseline level of psychopathology and previous treatment with high-dose antipsychotics.

• Rapid transition from a medication with significant anticholinergic properties to 1 without these properties may result in symptoms of activation, including restlessness, insomnia, and anxiety, which can be mistaken for worsening psychosis.

• Akathisia, a common adverse effect of aripiprazole, may masquerade as treatment-emergent worsening of psychotic symptoms.

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.1 However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.5 Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.5

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia12 and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).13 Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.14 In vitro data15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Clinical Point

Emergence of psychotic symptoms temporally associated with aripiprazole initiation does not imply causation

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)23 and the other report specifically excluded the possibility of akathisia.24 Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,26 initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Takeuchi et al14 aimed to establish predictors of worsening psychosis in a naturalistic setting where patients slowly transitioned to aripiprazole from previous antipsychotic treatment. Patients were required to be on a stable dose of an antipsychotic before participating in the study. Aripiprazole was started at 12 mg/d for 2 weeks with flexible dosing from weeks 2 to 52. Previous antipsychotic therapy was reduced biweekly by 25%. The incidence of worsening psychopathology after aripiprazole initiation was higher in the group of patients who had previously received high-dose antipsychotic therapy (average chlorpromazine equivalents [CPZE]: 727 mg/d) compared with the group on low dosages (average CPZE: 382 mg/d). It is possible that previous high-dose antipsychotic therapy was indicative of more significant baseline psychopathology; however, the worsened group and stabilized group had similar baseline Clinical Global Impressions-Severity scores.

Pae et al25 aimed to find predictors of worsening psychosis with aripiprazole in patients whose previous antipsychotic therapy was immediately discontinued. They found lower baseline disease severity was associated with significant worsening during the first month of aripiprazole treatment.

An early refill request for psychostimulants for your college-age patient

﻿Mr. R, age 18, who has been taking amphetamine/dextroamphetamine, 10 mg/d, twice a day, for attention-deficit/hyperactivity disorder since he was age 10, comes to see you shortly after beginning college asking to refill earlier than usual. He says his symptoms are worse since beginning college and he is finding it difficult to focus in class and keep up with the heavy course work. He says he has been taking an extra 10 mg when he “needs the extra boost.” He asks for an early refill and increased dosage. How do you proceed?

Switch to an extended release formulation and increase the dosage to 30 mg/d

Switch to lisdexamfetamine, 30 mg/d

Prescribe amphetamine/dextroamphetamine, 10 mg, on an as-needed basis

Tell Mr. R to take his current prescription as prescribed and discuss the dangers of stimulant abuse. Reassess his symptoms at the next visit.